The causes of the adverse responses to contrast media (CM) are not well understood but may involve CM-induced alterations of the central nervous system (CNS). The blood brain barrier (BBB) strictly controls access of substance to the CNS. The rate of cerebrospinal fluid (CSF) production is a key factor in eliminating substances from the CNS. These two factors thus maintain and control the chemical environment of the CNS. If either factor is disrupted, toxic manifestations could occur. Both factors can be altered by CM. Contrast media are up to several hundred times more toxic in the CNS than systemically, and are able to disrupt the BBB. Experiments in dogs from this laboratory show that moderate doses of both ionic and non-ionic intravenous CM substantially decrease CSF production. Therefore, CM might be expected to alter the environment of the CNS and result in toxicity. The mechanisms of CM effects on the production of CSF will be studied in the proposed work. Conscious and anesthetized laboratory animal models and in vitro preparations will be employed to determine: the mechanisms of CM-induced ecreased CSF production; the extent of CNS toxicity resulting from this action of CM; changes in the concentration, retention and kinetics of substances in the CNS caused by CM; enhancement by certain risk factors of CM-induced toxicity by additionally decreasing CSF production or by predisposing the BBB to damaging effects of CM; and if it is possible to protect from these effects of CM pharmacologically.